Lecture on the Antagonism between the Actions of Active Substances

Limits to the Antagonism 6eween Atrop usand Physostignia.-As both atropia and physostigma possess a number of separate actions, it was tot unreasonable to anticipate that several of them are not mutually antagonistic; and, therefore, that combinations of certain doses of the two substances may be administered whereby the non-antagonist actions will be produced in sufficient degrees of energy to be able to cause death. The possibility of a fatal result ensuing after the combined adminitration of the two substances in certain dose is also rendered probable by many ficts which show that several of their actions are of a similar nature. When a dose not greatly above the minimumlethal of the one is counteracted by a moderate dose of the other, these dmilar actions are not produced in sufficient intensity to become, even in combination, important toxic actions When, however, a dose con. siderably above the minimum-lethal of the one substance is given along with a large dose of the other, the similar actions may be produced in such intensity as to assume the importance of lethal actions. Guided by these considerations, I anticipated that the counteracting influence of atropia upon the lethal action of physotigma is successfully exerted only withit a limited range of doses, and that this range may be determined by experimental research. The task of making this determination was undertaken because it seemed likely that resuts would thereby be obtained of the greatest interest and novelty, in connexion not only with this special instance of counteraction, but also with the general subject of physlogical antagonism and its importat and direct bearing on the prInciples of therapeutics. In order to define the limits of the counteracting influence of atropia upon the lethal action of physostigma, three senes of expeiment were made. The chief objects of the first two of these were to n the maximum dose of physostigma that can be successfully antagonised by atropia, and the range of doses of atropia that can successfully antagonise lethal doses of physostigma. In each series, a constant interval of time was maintained between the administration of the two substances; but in the first atropia was administered five minutes before physostigma, while in the second physostigma was administered five minutes before atropia. In both of these series, experiments were made, in the first place, with the minimum-lethal dose of physostigma; and, in combination with it, various doses of atropia were administered, ranging from one that was too small to prevent the lethal action, through a number that were able to prevent death, until a dose was found whose administration resulted in death. Similar expenments were made with a dose of physostigma one-and-a-half times as large as the minimumlethal, then with one twice as large as the minimum-lethal, and so on, at the same rate of progression, until a dose was reached that was too large to be successfully antagonised by any dose of atropia. The chief object of the third series of experiments was to ascertain within what limits of time between the administration of the two substances successful antagonism occurs. In the experiments of this series, a constant dose of physostigma was given along with various doses of atropia; and with each dose of atropia several experiments were made, which differed from each other by a difference in the interval of time between the administration of the two substances. On